Crystal modifications of 1-(2,6-difluoro benzyl)-1H-1,2,3-triazole-4-carboxamide

ABSTRACT

The invention relates to the novel modification A or A′ of the compound 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide of the formula  
                 
 
     its use and pharmaceutical preparations comprising this crystal modification.

BACKGROUND OF THE INVENTION

[0001] The compound1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide of the formula

[0002] is described in the European Patent Application with thePublication No. 0 199 262 A2 (EP 199262), for example in Example 4.Valuable pharmacological properties are attributed to this compound;thus, it can be used, for example, as an antiepileptic. The compound1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide is obtainedaccording to EP 199262, starting from 2,6-difluorobenzyl azide via theformation of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid,the procedure being analogous to Example 2.

[0003] EP 199262 provides no information at all about possible crystalmodifications obtained. If the method according to the Example 4 is usedin conjunction with Example 2, the crude1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide product obtainedis finally crystallized from ethanol. However, EP 199262 gives noindication that such recrystallization is specifically to be applied, oron particular conditions that might be adopted. It has now surprisinglybeen found that the different crystal modifications (polymorphism)characterized below can be prepared by choice of specially selectedprocess conditions, for example through the choice of an appropriatesolvent for the recrystallization or the duration of therecrystallization.

DESCRIPTION OF THE INVENTION

[0004] 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide can beobtained in the novel crystal modifications A, A′, B and C. Thesecrystal modifications differ with respect to their thermodynamicstability, in their physical parameters, such as the absorption patternof IR and Raman spectra, in X-ray structure investigations and in theirpreparation processes.

[0005] The invention relates to the novel crystal modifications A andA′, their preparation and use in pharmaceutical preparations comprisingthis crystal modification.

[0006] The modification A′, compared with A, has defects in the crystallattice. These are detectable, for example, by X-ray analysis, e.g. bysmaller line spacings with otherwise predominantly identical lines orbands.

[0007] The novel crystal modification A of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide melts at 242° C.(239-245° C.).

[0008] In the FT infrared (FT-IR) spectrum (KBr pellet—transmissionmethod), modification A or A′ differs from modifications B and Cpredominantly in the shape and in the relative intensity of many bands.Particularly characteristic are the bands at 3412 cm⁻¹ and 3092 cm⁻¹[cf. FIG. 1], which are not present in the FT-IR spectra of themodifications B and C. In the range 4000-600 cm⁻¹, inter alia thefollowing bands are obtained for modification A: 3412, 3189, 3092, 1634,1560, 1473, 1397, 1325, 1300, 1284, 1235, 1125, 1053, 1036, 1014, 885,840, 799, 781, 723, 688 and 640 cm⁻¹. For example, the apparatus IFS 88(Bruker) can be used for the recording of each of the FT-IR spectra.

[0009] In the FT Raman spectrum (powder—reflection method 180°), themodification A or A′ differs from modifications B and C predominantly inthe shape and in the relative intensity of many bands. Particularlycharacteristic are the band at 1080 cm⁻¹ [cf. FIG. 2], which is notpresent in the Raman spectra of the modifications B and C. In the range3400-300 cm⁻¹, inter alia the following bands are obtained for themodification A: 3093, 2972, 1628, 1614, 1558, 1465, 1446, 1393, 1279,1245, 1147, 1080, 1061, 1036, 1014, 840, 724, 691, 667, 550, 499, 437and 368 cm⁻¹. For example, the apparatus RFS 100 (Bruker) can be usedfor the recording of each of the FT Raman spectra.

[0010] The novel modification A has an X-ray powder pattern withcharacteristic lines with interplanar spacings (d values) of 10.5 Å,5.14 Å, 4.84 Å, 4.55 Å, 4.34 Å, 4.07 Å, 3.51 Å, 3.48 Å, 3.25 Å, 3.19 Å,3.15 Å, 3.07 Å, 2.81 Å [cf. Table 1]. The measurement can be carriedout, for example, in transmission geometry on an FR 552 Guinier camerafrom Enraf-Nonius, Delft (The Netherlands), using copper Kα₁, radiation(wavelength λ=1.54060 Å). The patterns recorded on X-ray film weremeasured using an LS-18 line scanner from Johannsson, Taby (Sweden) andevaluated using the Scanpi software (P. E. Werner, University ofStockholm).

[0011] Characteristic for the novel modification A is the thermogram indifferential scanning calorimetry. It has an endothermic peak in therange from 230° C. to 260° C. The peak temperature is 239-245° C., andthe endothermic signal is 209 J/g+/−10 J/g. The measurement was carriedout on a Perkin Elmer DSC 7 in a closed pan with a heating rate of 20K/minute. The typical sample quantity is about 4 mg. As a typicaldistinguishing feature compared with the modifications B and C, thethermogram of the modification A has no further thermal signal.

[0012] Crystals fo the modification A′ have the same crystal structureas modification A. They differ from the modification A in the X-raypowder pattern in that they have slightly smaller line spacings betweenspecific pairs of lines. These are the pairs of lines with the followinginterplanar spacings: 3.68 Å and 3.64 Å, 3.51 Å and 3.48 Å, 3.19 Å and3.15 Å.

[0013] In the FT-IR spectrum (KBr pellet—transmission method), themodification B differs from the modification A or A′ and C predominantlyin the shape and in the relative intensity of many bands. Particularlycharacteristic is a band at 1678 cm⁻¹ [cf. FIG. 1], which is not to beobserved in the corresponding spectra of the modifications A and C. Inthe range 4000-600 cm⁻¹, inter alia the following bands are obtained forthe modification B: 3404, 3199, 3125, 1678, 1635, 1560, 1475, 1393,1357, 1322, 1286, 1237, 1051, 1036, 1028, 889, 837, 800, 719, 667 and645 cm¹. For example, the apparatus IFS 85 (Bruker) can be used forrecording of each of the FT-IR spectra.

[0014] In the FT Raman spectrum (powder—reflection method 180°), themodification B differs from the modifications A or A′ and Cpredominantly in the shape and in the relative intensity of many bands.Particularly characteristic are the bands at 3166 cm⁻¹ and 1086 cm⁻¹[cf. FIG. 2], which are not present in the Raman spectra of themodifications A and C. In the range 3400-300 cm⁻¹, inter alia thefollowing bands are obtained for the modification B: 3166, 3089, 2970,1678, 1628, 1614, 1559, 1464, 1441, 1391, 1275, 1244, 1147, 1086, 1062,1036, 1014, 839, 773, 724, 690, 668, 595, 549, 500, 493, 430 and 365cm⁻¹. For example, the apparatus RFS 100 (Bruker) can be used forrecording of each of the FT Raman spectra.

[0015] The modification B has an X-ray powder pattern withcharacteristic lines with interplanar spacings (d values) of 11.0 Å, 8.3Å, 5.18 Å, 4.88 Å, 4.80 Å, 4.42 Å, 4.33 Å, 4.19 Å, 4.12 Å, 3.81 Å, 3.50Å, 3.41 Å, 3.36 Å, 3.32 Å, 3.28 Å, 3.24 Å, 3.05 Å, 2.83 Å [cf. Table 1].

[0016] In the thermogram in differential scanning calorimetry, themodification B has, in addition to an endothermic signal in the rangefrom 230° C. to 260° C. (peak temperature 239-245° C.), a weak thermalsignal at 205° C. (180°-220° C.) as a typical distinguishing featurecompared with the modifications A or A′ and C.

[0017] In the FT-IR spectrum (KBr pellet—transmission method), themodification C differs from the modifications A or A′ and Bpredominantly in the shape and in the relative intensity of many bands.Particularly characteristic is a band at 3137 cm⁻¹ [cf. FIG. 1], whichis not to be observed in the corresponding spectra of the modificationsA and B.

[0018] In the range 4000-600 cm⁻¹, inter alia the following bands areobtained for the modification C: 3396, 3287, 3137, 1657, 1631, 1602,1559, 1475, 1392, 1323, 1287, 1237, 1122, 1104, 1047, 1035, 1012, 876,839, 797, 773, 729 and 653 cm⁻¹. For example, the apparatus IFS 85(Bruker) can be used for recording of each of the FT-IR spectra.

[0019] In the FT Raman spectrum (powder—reflection method 180°), themodification C differs from the modifications A or A′ and Bpredominantly in the shape and in the relative intensity of many bands.Particularly characteristic are the bands at 3137 cm⁻¹ and 1602 cm⁻¹[cf. FIG. 2], which are not present in the Raman spectra of themodifications A and B. In the range 3400-300 cm⁻¹, inter alia thefollowing bands are obtained for the modification C: 3137, 3080, 3012,2971, 1673, 1629, 1602, 1561, 1436, 1271, 1248, 1105, 1065, 1035, 1013,839, 800, 767, 726, 690, 672, 593, 549, 500, 492, 435 and 370 cm⁻¹. Forexample, the apparatus RFS 100 (Bruker) can be used for recording ofeach of the FT Raman spectra.

[0020] The modification C has an X-ray powder pattern withcharacteristic lines with interplanar spacings (d values) of 9.0 Å, 4.73Å, 4.65 Å, 3.75 Å, 3.54 Å, 3.42 Å, 3.25 Å [cf. Table 1]. In thethermogram in differential scanning calorimetry, the modification C has,in addition to an endothermic signal in the range of 230° C. to 260° C.(peak temperature 239-245° C.), a very broad, weak, exothermic signal inthe region of 180° C. compared with the modifications A or A′ and B.TABLE 1 Characterization of the modifications A, B and C (X-ray powderpatterns): Modification A: Modification B: Modification C: d [Å]Intensity d [Å] Intensity d [Å] Intensity 10.9 weak 11.0 medium 9.0medium 10.5 medium 8.3 medium 7.0 weak 6.6 weak 8.1 very weak 5.49 weak5.63 weak 5.68 very weak 5.11 very weak 5.25 weak 5.18 very strong 4.80weak 5.14 medium 5.11 weak 4.73 strong 4.94 weak 4.88 medium 4.65 verystrong 4.84 very strong 4.80 strong 4.47 very weak 4.55 strong 4.71 veryweak 4.19 very weak 4.42 very weak 4.61 weak 4.11 very weak 4.34 medium4.45 weak 3.98 very weak 4.23 very weak 4.42 strong 3.83 very weak 4.16weak 4.33 very strong 3.75 strong 4.07 medium 4.19 medium 3.73 weak 4.01weak 4.12 strong 3.54 medium 3.68 very weak 4.09 weak 3.50 weak 3.64very weak 3.99 very weak 3.42 strong 3.60 weak 3.95 very weak 3.25medium 3.56 weak 3.84 weak 2.88 very weak 3.51 medium 3.81 medium 2.80very weak 3.48 medium 3.65 weak 2.74 very weak 3.38 very weak 3.61 veryweak 2.67 very weak 3.25 strong 3.58 very weak 2.64 weak 3.19 medium3.54 weak 3.15 medium 3.50 medium 3.11 weak 3.47 very weak 3.07 medium3.41 medium 2.93 very weak 3.36 very strong 2.87 very weak 3.32 strong2.81 medium 3.28 medium 2.76 weak 3.24 medium 2.73 very weak 3.10 weak2.68 weak 3.07 weak 2.62 very weak 3.05 medium 2.53 weak 2.93 weak 2.43weak 2.88 weak 2.40 very weak 2.87 very weak 2.83 medium 2.66 weak 2.63very weak 2.55 weak 2.50 weak 2.46 weak 2.44 weak 2.37 weak 2.35 weak

[0021] Single Crystal X-Ray Analysis:

[0022] Crystal quality and unit cell of modifications A, B, and C wereverified by Weissenberg and precession photographs. The intensities weremeasured on a four-axis Nonius CAD-4 diffractometer. The structures weresolved with the SHELXS-97 and refined with the SHELXL-97 software.

[0023] Modification A

[0024] Space Group: Pna2₁—Orthorhombic

[0025] Cell Dimensions: a = 24.756 (5)Å b = 23.069 (4)Å c = 5.386 (1)Å v= 3075.9 Å³ Z = 12 D_(x) = 1.543 gcm⁻³ v per formula: V_(z) = 256.3 Å³

[0026] 9011 unique reflections; 2479 thereof significant with I>2σ (I).557 parameters refined. Position of all H atoms found by differenceFourier maps and refined isotropically. Reliability index R₁: 3.65% (wR₂for all 9011 reflections: 11.34%).

[0027] Modification B

[0028] Space Group: P 1—triclinic

[0029] Cell Dimensions: a = 5.326(1) Å b = 11.976(2) Å c = 17.355(3) Å α= 107.22(3)° β = 92.17(3)° γ = 102.11(3)° v = 1027.9 Å³ Z = 4 D_(x) =1.539 gcm⁻³ v per formula V_(z) = 257.0 Å³

[0030] 4934 unique reflections; 834 thereof significant with I>2σ (I).232 parameters refined. Position of all H atoms found by differenceFourier maps and refined isotropically. Reliability index R₁: 4.20% (wR₂for all 4934 reflections: 7.93%).

[0031] Modification C

[0032] Space Group: P2₁/C—monoclinic

[0033] Cell Dimensions: a = 10.982(2) Å b = 5.350(1) Å c = 17.945(3) Å v= 1053.9 Å³ β = 91.59(1)° D_(x) = 1.501 gcm⁻³ v per formula: Z = 4 V_(z)= 263.5 Å³

[0034] 3073 unique reflections; 1071 thereof significant with I>2σ (I).187 parameters refined. Position of all H atoms found by differenceFourier maps and refined isotropically. Reliability index R₁: 5.02% (wR₂for all 3073 reflections: 14.55%).

[0035] Modifications A, A′, B and C have valuable pharmacologicalproperties; in particular, they can be used for the treatment ofepilepsy.

[0036] The modification A or A′ has significant advantages compared withthe modification B and compared with the modification C. Thus, forexample, comprehensive thermodynamic investigations, such asthermomicroscopy, X-ray powder diffractometry, DSC, solubility tests andother experiments, have shown that the modification A or A′ surprisinglyhas substantially better thermodynamic stability than the modificationsB and C. Modification C, which can be obtained only under specificconditions, is the least stable of the three modifications. The crystalsof the modification C are converted into modification B at as low asroom temperature within a few weeks. The modification C is convertedeither into the modification A or A′ or into the modification B,depending on experimental conditions.

[0037] It is particularly important for drug that its pharmaceuticalformulation ensures high and reproducible stability over a long period.These preconditions are fulfilled by incorporation of the compound1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide of the crystalmodification A or A′, owing to its high thermodynamic stability. Inparticular, this is displayed in a solid pharmaceutical dosage form.

[0038] A constant stability also permits reproducible bioavailability ofan active ingredient. If an active ingredient is subjected to aconversion process, this may readily also cause the bioavailability tofluctuate, which is undesirable. Accordingly, pharmaceutical activeingredients or polymorphic forms thereof which are of primary interestfor pharmaceutical developments are those which exhibit high stabilityand do not have the above-mentioned disadvantages. The crystalmodification A or A′ fulfils these preconditions.

[0039] Furthermore, the modification A or A′ has, for example, a slowerdissolution rate in water or in gastric fluid (so-called “slow-releaseeffect”). This effect can be utilized primarily for long-term therapywhere a slow or delayed release is desired.

[0040] The invention relates to the modification A of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, characterized bythe following absorptions in the infrared spectrum (KBrpellet—transmission method): bands at 3092 cm⁻¹ and 3412 cm⁻¹.

[0041] The invention relates to the modification A of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, characterized bycharacteristic lines with interplanar spacings (d values) of 10.5 Å,5.14 Å, 4.84 Å, 4.55 Å, 4.34 Å, 4.07 Å, 3.51 Å, 3.48 Å, 3.25 Å, 3.19 Å,3.15 Å, 3.07 Å and 2.81 Å, determined by means of an X-ray powderpattern.

[0042] The invention relates to the modification A of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, characterized bythe characteristic lines with interplanar spacings (d values) as shownin Table 1.

[0043] The invention relates to the modification A of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, characterized byan endothermic peak in the range from 230° C. to 260° C., the peaktemperature being 239-245° C. and the endothermic signal being 209J/g+/−10 μg.

[0044] Furthermore, the invention relates to the crystal modification A′which, compared with modification A, has defects in the crystal lattice.The invention relates to the modification A′ which, compared withmodification A, has smaller line spacings between the pairs of lineswith interplanar spacings 3.68 Å and 3.64 Å, 3.51 Å and 3.48 Å, and 3.19Å and 3.15 Å.

[0045] The invention relates to the essentially pure form of themodification A or A′ of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide. The term“essentially pure form” means purity of >95%, in particular >98%,primarily >99%, based on the modification A or A′.

[0046] The invention relates to pharmaceutical preparations comprisingthe modification A or A′ of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide. The inventionrelates in particular to corresponding pharmaceutical preparations forthe treatment of epilepsy and subindications thereof. The inventionrelates to the use of the modification A or A′ of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide for thepreparation of pharmaceutical preparations, in particular for thetreatment of epilepsy and subindications thereof.

[0047] The novel modification A or A′ of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide can be used, forexample, in the form of pharmaceutical preparations which comprise atherapeutically effective amount of the active ingredient, if desiredtogether with inorganic or organic, solid or liquid, pharmaceuticallyusable carriers, which are suitable for enteral, for example oral, orparenteral administration. Furthermore, the novel modification A or A′of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide can be used inthe form of preparations which can be administered parenterally or ofinfusion solutions. The pharmaceutical preparations may be sterilizedand/or may comprise excipients, for example preservatives, stabilizers,wetting agents and/or emulsifiers, solubilizers, salts for regulatingthe osmotic pressure and/or buffers. The present pharmaceuticalpreparations comprise from about 0.1% to 100%, in particular from about1% to about 50%, of lyophilisates to about 100% of the activeingredient.

[0048] The invention also relates to the use of modification A or A′ of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide as a drug,preferably in the form of pharmaceutical preparations. The dosage maydepend on various factors, such as method of administration, species,age and/or individual condition. The doses to be administered daily arebetween about 0.25 and about 10 mg/kg in the case of oraladministration, and preferably between about 20 mg and about 500 mg forwarm-blooded species having a body weight of about 70 kg.

[0049] The preparation of modification A or A′ is carried out, forexample, as described in the embodiments below.

[0050] Preparation of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide

EXAMPLE 1

[0051] A suspension of methyl1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate (about 62 partsby weight), methanol (475.2 parts by weight) and anhydrous ammonia (29.4parts by weight) is stirred for about 24 hours at 50-55° C. in a closedvessel. The suspension is cooled to about 20° C. and stirred for about afurther 2 hours. The product is isolated by filtration, washed withmethanol (240 parts by weight) and dried at 40-60° C. in vacuo. Yield:57.2 parts by weight=98%. Modification A.

[0052] The starting compounds can be prepared, for example, as follows:

[0053] A mixture of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (167.1 partsby weight), methanol (552 parts by weight) and 96% sulfuric acid (35.7parts by weight) is stirred for about 5 hours at 60-66° C. Thesuspension is cooled to about 20° C. and stirred for about a further 2hours. The product is isolated by filtration and washed with methanol(198 parts by weight). A yield of about 160 parts by weight is obtainedby drying at 40-60° C. in vacuo.

EXAMPLE 2

[0054] 1 N sodium hydroxide solution (0.11 ml) is added to a mixture of4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole (2.20 g) and water (44ml) at an external temperature of 95-10° C. while stirring. After 90minutes, the suspension is cooled to 10° C. and the product is isolatedby filtration, washed with water and dried at about 60° C. in vacuo.1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide is obtained inthis manner; yield: 99.2% by weight. Modification A.

[0055] The starting material can be prepared, for example, as follows:

[0056] 4-Cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole

[0057] A mixture of 2,6-difluorobenzyl azide (34.2 g),2-chloroacrylonitrile (17.73 g) and water (125 ml) is stirred for 24hours at about 80° C. By increasing the external temperature to about130° C., excess 2-chloroacrylonitrile is distilled off. The semisolidmixture is cooled to about 40° C., cyclohexane (50 ml) is added to thesuspension and the mixture is brought to about 20° C. and stirred forabout 2 hours. The product is isolated by filtration and washed withcyclohexane (75 ml) and then with water (50 ml). The moist product ismixed with water (100 ml), the suspension is filtered and the product iswashed with water (50 ml) and dried at about 60° C. in vacuo. Yield:38.04 g=86%.

[0058] Examples of the Recrystallization of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide

EXAMPLE 3

[0059] 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide (75.0 g)is dissolved in formic acid (360 ml) at 50-55° C. by stirring. Thesolution is discharged in the course of 1 hour onto stirred methanol(375 ml) at about 20° C., a suspension forming. After stirring has beencontinued for 2 hours at about 200C, the product is isolated byfiltration, washed with methanol (750 ml) and dried at about 60° C. invacuo. Yield: 69.6 g=92.8%. Modification A.

EXAMPLE 4

[0060] 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide (22.86 kg)is dissolved in formic acid (111.6 kg) at 58-63° C. while stirring. Thesolution is discharged in the course of about 2 hours onto stirredmethanol (131.91) at 20-25° C., after which washing with formic acid(7.6 kg) is carried out. A suspension forms. After stirring has beencontinued for at least 3 hours at about 20° C., the product is isolatedby filtration and washed with methanol (187.5 I). By drying in vacuo atabout 60° C., the product is obtained as modification A in a yield of93-94%.

EXAMPLE 5

[0061] 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide (pureactive ingredient; 4.0 g) is dissolved in 96% ethanol (500 ml, withoutdenaturing agent) at about 80° C. while stirring. The solution isfiltered into a suction bottle (1 litre) at about 20° C. (glass suctionfilter, pore size 10-20 μm), a suspension forming. After stirring hasbeen continued for 5 minutes at about 20° C. and for 15 minutes at about0° C., the product is isolated by filtration (about 0° to about 20° C.).The solvent-moist product (9.6 g) is investigated without subsequentdrying. Modification A′.

FORMULATION EXAMPLE 1

[0062] Film-coated tablets each containing, for example, 100, 200 or 400mg of modification A or A′ of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide with thefollowing composition per dosage unit: mg mg mg Core material Activeingredient 100.00 200.00 400.00 Anhydrous, colloidal silica 0.88 1.753.5 Microcrystalline cellulose 36.62 73.25 146.50 Hydroxypropylmethyl-5.00 10.00 20.00 cellulose Lactose 20.00 40.00 80.00 Magnesium stearate2.00 4.00 8.00 Maize starch 10.00 20.00 40.00 Sodium carboxymethyl- 5.0010.00 20.00 cellulose Sodium laurylsulfate 0.50 1.00 2.00 Film coatHydroxypropylmethyl- 3.22 6.43 12.87 cellulose Red iron oxide 0.04 0.090.18 Polyethylene glycol 8000, 0.58 1.16 2.32 flakes Talc 2.33 4.66 9.31Titanium dioxide 0.83 1.66 3.32

[0063] The active ingredient is granulated with demineralised water.Milled lactose, maize starch, Avicel PH 102, cellulose-HP-M-603 andsodium laurylsulfate are added to the above mixture and granulated withdemineralised water.

[0064] The moist material is dried and milled. After the addition of theremaining ingredients, the homogeneous mixture is compressed to givetablet cores having the stated active ingredient content.

[0065] The tablet cores are coated with the film coat which is formedfrom the appropriate ingredients, the latter being dissolved or beingsuspended in water or in small amounts of ethanol with 5% ofisopropanol.

DESCRIPTION OF THE FIGURES

[0066]FIG. 1 shows the FT-IR spectra of the KBr pellets of modificationsA, B and C.

[0067]FIG. 2 shows the FT-Raman spectra of the powder of modification A,B and C.

[0068] In both Figures, the modification A is denoted by the symbol *,the modification B by the symbol ** and the modification C by the symbol***.

1. Modification A of the compound1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide of the formula

characterized by characteristic lines at interplanar spacings (d values)of 10.5 Å, 5.14 Å, 4.84 Å, 4.55 Å, 4.34 Å, 4.07 Å, 3.51 Å, 3.48 Å, 3.25Å, 3.19 Å, 3.15 Å, 3.07 Å, 2.81 a, determined by means of an x-raypowder pattern.
 2. Modification according to claim 1, characterized byan X-ray powder pattern having the following characteristic lines atinterplanar spacings (d values) of 10.9 Å (weak), 10.5 Å (medium), 6.6 Å(weak), 5.63 Å (weak), 5.25 Å (weak), 5.14 Å (medium), 4.94 Å (weak),4.84 Å (very strong), 4.55 Å (strong), 4.42 Å (very weak), 4.34 Å(medium), 4.23 Å (very weak), 4.16 Å (weak), 4.07 Å (medium), 4.01 Å(weak), 3.68 Å (very weak), 3.64 Å (very weak), 3.60 Å (weak), 3.56 Å(weak), 3.51 Å (medium), 3.48 Å (medium), 3.38 Å (very weak), 3.25 Å(strong), 3.19 Å (medium), 3.15 Å (medium), 3.11 Å (weak), 3.07 Å(medium), 2.93 Å (very weak), 2.87 Å (very weak), 2.81 Å (medium), 2.76Å (weak), 2.73 Å (very weak), 2.68 Å (weak), 2.62 Å (very weak), 2.53 Å(weak), 2.43 Å (weak), 2.40 Å (very weak).
 3. Modification according toclaim 1 or 2, characterized by the following absorptions in the FT-IRspectrum (KBr pellet—transmission method) 3092 cm⁻¹ and 3412 cm⁻¹. 4.Modification according to claim 3, characterized by the followingabsorptions in the FT-IR spectrum (KBr pellet—transmission method):3412, 3189, 3092, 1634, 1560, 1473, 1397, 1325, 1300, 1284, 1235, 1125,1053, 1036, 1014, 885, 840, 799, 781, 723, 688 and 640 cm⁻¹. 5.Modification according to any one of claims 1-4, characterized by thefollowing absorptions in the FT-Raman spectrum (powder—reflection method180°): 3093, 2972, 1628, 1614, 1558, 1465, 1446, 1393, 1279, 1245, 1147,1080, 1061, 1036, 1014, 840, 724, 691, 667, 550, 499, 437 and 368 cm⁻¹.6. Modification A according to any one of claims 1-5, characterized byan endothermic peak in the range from 230° C. to 260° C., the peaktemperature being 239-245° C. and the endothermic signal being 209J/g+/−10 J/g.
 7. Modification A′ of the compound1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, characterized inthat it is identical to the modification A according to any one ofclaims 1-6 but has defects in the crystal lattice.
 8. Modification A′according to claim 7, characterized by line spacings, smaller comparedto modification A according to any one of claims 1-6, between the pairsof lines at interplanar spacings 3.68 Å and 3.64 Å, 3.51 Å and 3.48 Å,and 3.19 Å and 3.15 Å.
 9. Modification A or A′ according to any one ofclaims 1-8 in essentially pure form.
 10. Pharmaceutical preparationscomprising the modification A or A′ of the compound1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide according to anyone of claims 1-9 and pharmaceutically usable excipients and additives.11. Use of the modification A or A′ of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide according to anyone of claims 1-9 as a pharmaceutical preparation.
 12. Use of themodification A or A′ of1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide according to anyone of claims 1-9 for the preparation of pharmaceutical preparations forthe treatment of epilepsy and subindications thereof.
 13. A modificationof the compound 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamidecharacterized by bands at 3412 cm⁻¹ and 3092 cm⁻¹ in the FT-IR spectrum.14. A modification of the compound1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide characterized bya band at 1080 cm⁻¹ in the FT-Raman spectrum.
 15. A pharmaceuticalpreparation comprising a modification according to claim 13 or 14 andpharmaceutically usable excipients and additives.